The accumulation of heritable genetic and epigenefic changes that result in loss of funcfion of tumor suppressors and/or inappropriate activation of proto-oncogenes is a hallmark of cancer. The goals of the Molecular Genetics and Epigenetics Program (GEN) are to understand the molecular mechanisms that underiie these defects and to uncover new targets for therapy, diagnosis, prognosis, and prevention. The Program capitalizes on the large number of outstanding invesfigators at UVA with research expertise in chromafin architecture, transcription, replicafion. mutation, repair, and cellular checkpoints in cancer. The Members are organized around four main themes: (1) Chromosome funcfion, malfunction, and cellular checkpoints; (2) Epigenefics and cancer; (3) Signaling and gene expression in cancer; and (4) Bioinformatics: mining informafion from human genomes. The Program is led by Joyce L. Hamlin, PhD, an expert in mammalian DNA replicafion and large-scale chromosome rearrangements in tumor cells; and by Anindya Dutta, MD, PhD a leader in the replicafion and cell cycle fields. Dr. Dutta has focused more recenfiy on the role of microRNAs in tumorigenesis. Through its acfivities. GEN provides a formal mechanism for fostering intellectual exchange and collaboration among its Members. The Program currently consists of 32 Full Members and 6 Associate Members from 11 different departments. Twenty one of these individuals are new to the Program or to UVA since the last renewal, and they bring considerable expertise in the bioinformatics of microarray and deep-sequencing data, large-scale genomic rearrangements (including aneuploidy). and the molecular effects of radiafion and cellular responses to radiation. Importanfiy for this renewal, GEN has added a significant cohort of translafional and clinical invesfigators whose research focus is on particular tumor types, including lung and brain tumors, or on radiafion damage. Total extramural funding for the Program exceeds $14.8 million, including $3.4 million from the Nafional Cancer Institute (NCI) and an award from the American Cancer Society. Program Members have produced 390 cancer-relevant publicafions, of which 32% were inter-programmatic and 18% were intra-programmatic since the last renewal. In addition. Program Members participate in multi-invesfigator and collaborative Nafional Insfitutes of Health research awards, including 18 grants from NCI.